Summary
Introduction: This thesis reports the surveillance response of the EUROCAT network of
population based registries for surveillance of congenital anomalies to the 2009 H1Nl
influenza pandemic. Due to the controversy around vaccinating 1st trimester pregnant
women, the relationship between pandemic influenza outbreaks and congenital anomalies
(CA) deserves attention. The purpose of this thesis is to improve public health practice by
investigating the effect of the 2009 HiNl influenza pandemic on CA prevalence in Europe
and exploring the pandemic vaccination policy and policy making with respect to pregnancy.
Methods: Systematic review of 44 studies and meta-analysis of 21 studies on influenza and
CA was performed. Since seasonality can confound analyses of influenza and CA, pre-pandemic
original analysis of seasonality of births and CA was performed according to
estimated month of conception, enrolling 20 EUROCAT congenital anomaly registries from
14 countries covering 366,000 births annually over 2000-2009.
The effect of 2009 H1N1 pandemic influenza and seasonal influenza exposure during critical
periods of organogenesis on CA prevalence was analysed by an ecological time series study,
enrolling 15 registries from 10 countries covering 364,000 births annually over 2007-2010
and using WHO influenza surveillance data. Case-malformed control analysis was performed
to compare exposure to pandemic influenza and its co-exposures between CA subgroups,
enrolling 11 registries from 9 countries covering 213,000 births annually over 2009-2010.
European pandemic policies with respect to pregnancy were surveyed by sending
questionnaires to EUROCAT registry leaders and European Departments of Health. The
results of the policy survey were investigated by policy analysis using content analysis of the
minutes and related documents describing British and Dutch decision making processes.
Results: Meta-analysis of literature associated a wide range of CA with influenza including
any CA (OR 2.25, 95% CI: 1.77-2.85), congenital heart disease (1.84, 1.50-2.26), neural tube
defects (3.61, 2.23-5.82) and cleft lip (3.00, 2.12-4.25). Seasonality analysis detected
seasonal peaks in the prevalences of all births (+4% compared to average in late September
conceptions) and a number of CA including CA previously associated with influenza (+3%,
June). Solely situs inversus prevalence was increased during influenza season (+35%,
December). Ecological time series analysis did not detect an increased prevalence of CA
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among pregnancies conceived during the 2009 influenza pandemic (ARR 1.03, 0.97-1.09).
Situs inversus prevalence was increased during 2007-2010 influenza outbreaks (ARR 2.06,
1.02-4.15) and statistically non-significant increases were witnessed for all situs anomalies.
Case-malformed control analysis detected an increase in upper respiratory tract exposure
among pregnancies resulting in neural tube defects (AOR 2.00, 1.03-2.90), but this was
based on data from a single registry and contradicted the findings of the ecological time
series analysis (ARR 0.91, 0.70-1.19). Very few individual exposures had been recorded for
pandemic influenza vaccine (n=5) or neuraminidase inhibitors (n=6) among CA registrations.
Replies to the policy survey were received from 24 European countries of which 12 solely
vaccinated 2nd and 3rd trimester pregnant women while 8 vaccinated pregnant women of
any trimester. These differences were further investigated by policy analysis and limitations
in evidence (in particular with respect to pandemic influenza vaccine and CA) were
identified to be an important factor in causing these varying vaccination policies.
Discussion and conclusion: The ecological time series analysis of the pandemic season did
not find the increase in CA expected on the basis of the meta-analysis results, possibly due
to biases leading to dilution and/or differences between populations, or lack of an
underlying relationship with influenza. Ascertaining influenza exposure and unravelling
influenza exposure from its co-exposures such as antivirals is a challenge for epidemiological
studies. Based on the results of the seasonality study and ecological time series study, a
hypothesis that situs anomalies can be related to either influenza or its co-exposures has
been generated.
The unknown effect of pandemic influenza vaccine on the fetus was a problem for European
pandemic policy making and investigating the relationships between antivirals, influenza
vaccine and CA using improved exposure data are urgent research priorities.